HHS Public Access Author manuscript Author Manuscript
J Hosp Med. Author manuscript; available in PMC 2016 June 15. Published in final edited form as: J Hosp Med. 2016 January ; 11(1): 56–61. doi:10.1002/jhm.2449.
Fecal Microbiota Transplantation for the Treatment of Clostridium difficile Infection Krishna Rao, MD1,2 and Nasia Safdar, MD, PhD.3,* 1Division
of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
Author Manuscript
2Division
of Infectious Diseases, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA 3William
S. Middleton Memorial Veterans Hospital and the Section of Infectious Diseases, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
Abstract
Author Manuscript
Clostridium difficile, a major cause of healthcare-associated diarrhea due to perturbation of the normal gastrointestinal microbiome, is responsible for significant morbidity, mortality, and healthcare expenditures. The incidence and severity of C. difficile infection (CDI) is increasing and recurrent disease is common. Recurrent infection can be difficult to manage with conventional antibiotic therapy. Fecal microbiota transplantation (FMT), which involves instillation of stool from a healthy donor into the gastrointestinal tract of the patient, restores the gut microbiome to a healthy state. FMT has emerged as a promising new treatment for CDI. There are limited data on FMT for treatment of primary CDI, but FMT appears safe and effective for recurrent CDI. The safety and efficacy of FMT in patients with severe primary or recurrent CDI has not been established. Patients with inflammatory bowel disease (IBD) who undergo FMT for CDI may be at increased risk of IBD flare and caution should be exercised with use of FMT in that population. The long-term safety of FMT is unknown; thus, rigorously conducted prospective studies are needed.
Introduction Author Manuscript
Epidemiology and pathogenesis Symptomatic Clostridium difficile infection (CDI) results when C. difficile, a Gram-positive bacillus that is an obligate-anaerobe, produces cytotoxins TcdA and TcdB, causing epithelial and mucosal injury in the gastrointestinal tract.1 Though it was first identified in 1978 as the causative agent of pseudomembranous colitis and several effective treatments have
*
Corresponding author: Section of Infectious Diseases, Department of Medicine, University of Wisconsin School of Medicine and Public Health, MFCB, 1685 Highland Avenue, Madison, Wisconsin 53705, USA. [email protected]. Phone: (608) 213-4075. Fax: (608) 263-4464. Conflicts of Interest The authors have nothing to disclose.
Rao and Safdar
Page 2
Author Manuscript
subsequently been discovered,2 nearly three decades later C. difficile remains a major nosocomial pathogen. C. difficile is the most frequent infectious cause of healthcareassociated diarrhea and causes toxin mediated infection. The incidence of CDI in the United States has increased dramatically, especially in hospitals and nursing homes where there are now nearly 500,000 new cases and 30,000 deaths per year.3–6 This increased burden of disease is due both to the emergence of several strains that have led to a worldwide epidemic7 and to a predilection for CDI in older adults, who constitute a growing proportion of hospitalized patients.8 Ninety-two percent of CDI-related deaths occur in adults >65 years,9 and the risk of recurrent CDI is 2-fold higher with each decade of life.10 It is estimated that CDI is responsible for $1.5 billion in excess healthcare costs each year in the US,11 and that much of the additional cost and morbidity of CDI is due to recurrence, with around 83,000 cases per year.6
Author Manuscript
The human gut microbiota which is a diverse ecosystem consisting of thousands of bacterial species,12 protects against invasive pathogens such as C. difficile.13, 14 The pathogenesis of CDI requires disruption of the gut microbiota before onset of symptomatic disease,15 and exposure to antibiotics is the most common precipitant (Figure 1).16 Following exposure, the manifestations can vary from asymptomatic colonization, to a self-limited diarrheal illness, to a fulminant, life-threatening colitis.1 Even among those that recover, recurrent disease is common.10 A first recurrence will occur in 15–20% of successfully treated patients, a second recurrence will occur in 45% of those patients, and up to 5% of all patients enter a prolonged cycle of CDI with multiple recurrences.17–19 The need for better treatment modalities: rationale
Author Manuscript Author Manuscript
Conventional treatments (Table 1) utilize antibiotics with activity against C. difficile20, 21 but these antibiotics have activity against other gut bacteria, limiting the ability of the microbiota to fully recover following CDI and predisposing patients to recurrence.22 Traditional treatments for CDI result in a high incidence of recurrence (35%), with up to 65% of these patients that are again treated with conventional approaches developing a chronic pattern of recurrent CDI.23 Though other factors may also explain why patients have recurrence (such as low serum antibody response to C. difficile toxins,24 use of medications such as proton pump inhibitors,10 and the specific strain of C. difficile causing infection10, 21), restoration of the gut microbiome through fecal microbiota transplantation (FMT) is the treatment strategy that has garnered the most attention and has gained acceptance among practitioners in the treatment of recurrent CDI when conventional treatments have failed.25 A review of the practices and evidence for use of FMT in the treatment of CDI in hospitalized patients is presented here, with recommendations shown in Table 2.
Overview of FMT FMT is not new to modern times as there are reports of its use in ancient China for various purposes.26 It was first described as a treatment for pseudomembranous colitis in the 1950s27 and in the past several years the use of FMT for CDI has increasingly gained acceptance as a safe and effective treatment. The optimal protocol for FMT is unknown:
J Hosp Med. Author manuscript; available in PMC 2016 June 15.
Rao and Safdar
Page 3
Author Manuscript
there are numerous published methods of stool preparation, infusion, and recipient and donor preparation. Diluents include tap water, normal saline, or even yogurt.23, 28, 29 Sites of instillation of the stool include the stomach, small intestine and large intestine.23, 29, 30 Methods of recipient preparation for the infusion include cessation of antibiotic therapy for 24–48 hours prior to FMT, a bowel preparation or lavage, and use of antimotility agents, such as loperamide, to aid in retention of transplanted stool.28 Donors may include friends or family members of the patients or one or more universal donors for an entire center. In both cases, screening for blood-borne and fecal pathogens is performed before one can donate stool, though the tests performed vary between centers. FMT has been performed in both inpatient and outpatient settings, and a published study that instructed patients on selfadministration of fecal enema at home also demonstrated success.30
Author Manuscript
Although there are numerous variables to consider in designing a protocol, as discussed further below it is encouraging that FMT appears to be highly effective regardless of the specific details of the protocol.28 If the first procedure fails, evidence suggests a second or third treatment can be quite effective.28 In a recent advance, successful FMT via administration of frozen stool oral capsules has been demonstrated,31 which potentially removes many system- and patient-level barriers to receipt of this treatment.
Clinical Evidence for Efficacy of FMT in Treatment of CDI Recurrent CDI
Author Manuscript Author Manuscript
The clinical evidence for FMT is most robust for recurrent CDI, consisting of case reports or case series, recently aggregated by two large systematic reviews, as well as several clinical trials.23, 29 Gough et al. published the larger of the two reviews with data from 317 patients treated via FMT for recurrent CDI,23 including FMT via retention enema (35%), colonoscopic infusion (42%), and gastric infusion (23%). Though the authors noted differences in resolution proportions among routes of infusion, types of donors, and types of infusates, it is not possible to draw definite conclusions form these data given their anecdotal nature. Regardless of the specific protocol’s details, 92% of patients in the review had resolution of recurrent CDI overall after one or more treatments, with 89% improving after only one treatment. Another systematic review of FMT, both for CDI and non-CDI indications, reinforced its efficacy in CDI and overall benign safety profile.32 Other individual case series and reports of FMT for CDI not included in these reviews have been published; they too demonstrate an excellent resolution rate.33–38 As with any case reports / series, generalizing from these data to arrive at conclusions about the safety and efficacy of FMT for CDI is limited by potential confounding and publication bias; thus, there emerged a need for high-quality prospective trials. The first randomized, controlled clinical trial (RCT) of FMT for recurrent CDI was reported in 2013.39 Three treatment groups were compared: vancomycin for 5 days followed by FMT (n=16), vancomycin alone for 14 days (n=13), or vancomycin for 14 days with bowel lavage (n=13). Despite a strict definition of cure (absence of diarrhea or persistent diarrhea from another cause with three consecutive negative stool tests for C. difficile toxin), the study was stopped early after an interim analysis due to resolution of CDI in 94% of patients in the
J Hosp Med. Author manuscript; available in PMC 2016 June 15.
Rao and Safdar
Page 4
Author Manuscript
FMT arm (81% after just one infusion) versus 23–31% in the others. Off-protocol FMT was offered to the patients in the other two groups and 83% of them were also cured. Youngster et al. conducted a pilot RCT with 10 patients in each group where patients were randomized to receive FMT via either colonoscopy or nasogastric tube from a frozen fecal suspension and no difference in efficacy was seen between administration routes, with an overall cure rate of 90%.40 Subsequently, Youngster et al. conducted an open-label noncomparative study with frozen fecal capsules for FMT in 20 patients with recurrent CDI.31 Resolution occurred in 14 (70%) patients after a single treatment and four of the six nonresponders had resolution upon retreatment for an overall efficacy of 90%.
Author Manuscript
Finally, Cammarota et al. conducted an open-label RCT on FMT for recurrent CDI,41 comparing FMT to a standard course of vancomycin for ten days followed by pulsed dosing every 2–3 days for three weeks. The study was stopped after a 1-year interim analysis as 18 of 20 patients (90%) treated by FMT exhibited resolution of CDI-associated diarrhea compared to only five of 19 patients (26%) in the vancomycin-treated group (P
J Hosp Med. Author manuscript; available in PMC 2016 June 15. Published in final edited form as: J Hosp Med. 2016 January ; 11(1): 56–61. doi:10.1002/jhm.2449.
Fecal Microbiota Transplantation for the Treatment of Clostridium difficile Infection Krishna Rao, MD1,2 and Nasia Safdar, MD, PhD.3,* 1Division
of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
Author Manuscript
2Division
of Infectious Diseases, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA 3William
S. Middleton Memorial Veterans Hospital and the Section of Infectious Diseases, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
Abstract
Author Manuscript
Clostridium difficile, a major cause of healthcare-associated diarrhea due to perturbation of the normal gastrointestinal microbiome, is responsible for significant morbidity, mortality, and healthcare expenditures. The incidence and severity of C. difficile infection (CDI) is increasing and recurrent disease is common. Recurrent infection can be difficult to manage with conventional antibiotic therapy. Fecal microbiota transplantation (FMT), which involves instillation of stool from a healthy donor into the gastrointestinal tract of the patient, restores the gut microbiome to a healthy state. FMT has emerged as a promising new treatment for CDI. There are limited data on FMT for treatment of primary CDI, but FMT appears safe and effective for recurrent CDI. The safety and efficacy of FMT in patients with severe primary or recurrent CDI has not been established. Patients with inflammatory bowel disease (IBD) who undergo FMT for CDI may be at increased risk of IBD flare and caution should be exercised with use of FMT in that population. The long-term safety of FMT is unknown; thus, rigorously conducted prospective studies are needed.
Introduction Author Manuscript
Epidemiology and pathogenesis Symptomatic Clostridium difficile infection (CDI) results when C. difficile, a Gram-positive bacillus that is an obligate-anaerobe, produces cytotoxins TcdA and TcdB, causing epithelial and mucosal injury in the gastrointestinal tract.1 Though it was first identified in 1978 as the causative agent of pseudomembranous colitis and several effective treatments have
*
Corresponding author: Section of Infectious Diseases, Department of Medicine, University of Wisconsin School of Medicine and Public Health, MFCB, 1685 Highland Avenue, Madison, Wisconsin 53705, USA. [email protected]. Phone: (608) 213-4075. Fax: (608) 263-4464. Conflicts of Interest The authors have nothing to disclose.
Rao and Safdar
Page 2
Author Manuscript
subsequently been discovered,2 nearly three decades later C. difficile remains a major nosocomial pathogen. C. difficile is the most frequent infectious cause of healthcareassociated diarrhea and causes toxin mediated infection. The incidence of CDI in the United States has increased dramatically, especially in hospitals and nursing homes where there are now nearly 500,000 new cases and 30,000 deaths per year.3–6 This increased burden of disease is due both to the emergence of several strains that have led to a worldwide epidemic7 and to a predilection for CDI in older adults, who constitute a growing proportion of hospitalized patients.8 Ninety-two percent of CDI-related deaths occur in adults >65 years,9 and the risk of recurrent CDI is 2-fold higher with each decade of life.10 It is estimated that CDI is responsible for $1.5 billion in excess healthcare costs each year in the US,11 and that much of the additional cost and morbidity of CDI is due to recurrence, with around 83,000 cases per year.6
Author Manuscript
The human gut microbiota which is a diverse ecosystem consisting of thousands of bacterial species,12 protects against invasive pathogens such as C. difficile.13, 14 The pathogenesis of CDI requires disruption of the gut microbiota before onset of symptomatic disease,15 and exposure to antibiotics is the most common precipitant (Figure 1).16 Following exposure, the manifestations can vary from asymptomatic colonization, to a self-limited diarrheal illness, to a fulminant, life-threatening colitis.1 Even among those that recover, recurrent disease is common.10 A first recurrence will occur in 15–20% of successfully treated patients, a second recurrence will occur in 45% of those patients, and up to 5% of all patients enter a prolonged cycle of CDI with multiple recurrences.17–19 The need for better treatment modalities: rationale
Author Manuscript Author Manuscript
Conventional treatments (Table 1) utilize antibiotics with activity against C. difficile20, 21 but these antibiotics have activity against other gut bacteria, limiting the ability of the microbiota to fully recover following CDI and predisposing patients to recurrence.22 Traditional treatments for CDI result in a high incidence of recurrence (35%), with up to 65% of these patients that are again treated with conventional approaches developing a chronic pattern of recurrent CDI.23 Though other factors may also explain why patients have recurrence (such as low serum antibody response to C. difficile toxins,24 use of medications such as proton pump inhibitors,10 and the specific strain of C. difficile causing infection10, 21), restoration of the gut microbiome through fecal microbiota transplantation (FMT) is the treatment strategy that has garnered the most attention and has gained acceptance among practitioners in the treatment of recurrent CDI when conventional treatments have failed.25 A review of the practices and evidence for use of FMT in the treatment of CDI in hospitalized patients is presented here, with recommendations shown in Table 2.
Overview of FMT FMT is not new to modern times as there are reports of its use in ancient China for various purposes.26 It was first described as a treatment for pseudomembranous colitis in the 1950s27 and in the past several years the use of FMT for CDI has increasingly gained acceptance as a safe and effective treatment. The optimal protocol for FMT is unknown:
J Hosp Med. Author manuscript; available in PMC 2016 June 15.
Rao and Safdar
Page 3
Author Manuscript
there are numerous published methods of stool preparation, infusion, and recipient and donor preparation. Diluents include tap water, normal saline, or even yogurt.23, 28, 29 Sites of instillation of the stool include the stomach, small intestine and large intestine.23, 29, 30 Methods of recipient preparation for the infusion include cessation of antibiotic therapy for 24–48 hours prior to FMT, a bowel preparation or lavage, and use of antimotility agents, such as loperamide, to aid in retention of transplanted stool.28 Donors may include friends or family members of the patients or one or more universal donors for an entire center. In both cases, screening for blood-borne and fecal pathogens is performed before one can donate stool, though the tests performed vary between centers. FMT has been performed in both inpatient and outpatient settings, and a published study that instructed patients on selfadministration of fecal enema at home also demonstrated success.30
Author Manuscript
Although there are numerous variables to consider in designing a protocol, as discussed further below it is encouraging that FMT appears to be highly effective regardless of the specific details of the protocol.28 If the first procedure fails, evidence suggests a second or third treatment can be quite effective.28 In a recent advance, successful FMT via administration of frozen stool oral capsules has been demonstrated,31 which potentially removes many system- and patient-level barriers to receipt of this treatment.
Clinical Evidence for Efficacy of FMT in Treatment of CDI Recurrent CDI
Author Manuscript Author Manuscript
The clinical evidence for FMT is most robust for recurrent CDI, consisting of case reports or case series, recently aggregated by two large systematic reviews, as well as several clinical trials.23, 29 Gough et al. published the larger of the two reviews with data from 317 patients treated via FMT for recurrent CDI,23 including FMT via retention enema (35%), colonoscopic infusion (42%), and gastric infusion (23%). Though the authors noted differences in resolution proportions among routes of infusion, types of donors, and types of infusates, it is not possible to draw definite conclusions form these data given their anecdotal nature. Regardless of the specific protocol’s details, 92% of patients in the review had resolution of recurrent CDI overall after one or more treatments, with 89% improving after only one treatment. Another systematic review of FMT, both for CDI and non-CDI indications, reinforced its efficacy in CDI and overall benign safety profile.32 Other individual case series and reports of FMT for CDI not included in these reviews have been published; they too demonstrate an excellent resolution rate.33–38 As with any case reports / series, generalizing from these data to arrive at conclusions about the safety and efficacy of FMT for CDI is limited by potential confounding and publication bias; thus, there emerged a need for high-quality prospective trials. The first randomized, controlled clinical trial (RCT) of FMT for recurrent CDI was reported in 2013.39 Three treatment groups were compared: vancomycin for 5 days followed by FMT (n=16), vancomycin alone for 14 days (n=13), or vancomycin for 14 days with bowel lavage (n=13). Despite a strict definition of cure (absence of diarrhea or persistent diarrhea from another cause with three consecutive negative stool tests for C. difficile toxin), the study was stopped early after an interim analysis due to resolution of CDI in 94% of patients in the
J Hosp Med. Author manuscript; available in PMC 2016 June 15.
Rao and Safdar
Page 4
Author Manuscript
FMT arm (81% after just one infusion) versus 23–31% in the others. Off-protocol FMT was offered to the patients in the other two groups and 83% of them were also cured. Youngster et al. conducted a pilot RCT with 10 patients in each group where patients were randomized to receive FMT via either colonoscopy or nasogastric tube from a frozen fecal suspension and no difference in efficacy was seen between administration routes, with an overall cure rate of 90%.40 Subsequently, Youngster et al. conducted an open-label noncomparative study with frozen fecal capsules for FMT in 20 patients with recurrent CDI.31 Resolution occurred in 14 (70%) patients after a single treatment and four of the six nonresponders had resolution upon retreatment for an overall efficacy of 90%.
Author Manuscript
Finally, Cammarota et al. conducted an open-label RCT on FMT for recurrent CDI,41 comparing FMT to a standard course of vancomycin for ten days followed by pulsed dosing every 2–3 days for three weeks. The study was stopped after a 1-year interim analysis as 18 of 20 patients (90%) treated by FMT exhibited resolution of CDI-associated diarrhea compared to only five of 19 patients (26%) in the vancomycin-treated group (P
